Selective Inhibition of DNA Polymerase β by a Covalent Inhibitor

2021 ◽  
Author(s):  
Shelby C. Yuhas ◽  
Daniel J. Laverty ◽  
Huijin Lee ◽  
Ananya Majumdar ◽  
Marc M. Greenberg
Keyword(s):  
Dna Polymerase ◽  
Selective Inhibition ◽  
Dna Polymerase Β ◽  
Covalent Inhibitor

scholarly journals The human checkpoint sensor and alternative DNA clamp Rad9–Rad1–Hus1 modulates the activity of DNA ligase I, a component of the long-patch base excision repair machinery

2005 ◽  
Vol 389 (1) ◽  
pp. 13-17 ◽  
Author(s):  
Ekaterina SMIRNOVA ◽  
Magali TOUEILLE ◽  
Enni MARKKANEN ◽  
Ulrich HÜBSCHER
Keyword(s):  
Quality Control ◽  
Dna Polymerase ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Dna Ligase ◽  
Dna Polymerase Β ◽  
Flap Endonuclease 1 ◽  
Important Target ◽  
Dna Ligase I ◽  
Base Excision

The human checkpoint sensor and alternative clamp Rad9–Rad1–Hus1 can interact with and specifically stimulate DNA ligase I. The very recently described interactions of Rad9–Rad1–Hus1 with MutY DNA glycosylase, DNA polymerase β and Flap endonuclease 1 now complete our view that the long-patch base excision machinery is an important target of the Rad9–Rad1–Hus1 complex, thus enhancing the quality control of DNA.

scholarly journals DNA polymerase β outperforms DNA polymerase γ in key mitochondrial base excision repair activities

DNA Repair ◽  
2021 ◽  
Vol 99 ◽  
pp. 103050
Author(s):  
Beverly A. Baptiste ◽  
Stephanie L. Baringer ◽  
Tomasz Kulikowicz ◽  
Joshua A. Sommers ◽  
Deborah L. Croteau ◽  
...  
Keyword(s):  
Dna Polymerase ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Dna Polymerase Β ◽  
Base Excision ◽  
Dna Polymerase Γ

scholarly journals Molecular disruption of DNA polymerase β for platinum sensitisation and synthetic lethality in epithelial ovarian cancers

Oncogene ◽  
2021 ◽  
Author(s):  
Reem Ali ◽  
Adel Alblihy ◽  
Islam M. Miligy ◽  
Muslim L. Alabdullah ◽  
Mansour Alsaleem ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Dna Polymerase ◽  
Synthetic Lethality ◽  
Ovarian Cancer Cells ◽  
Dna Polymerase Β ◽  
Mesenchymal Transition ◽  
Platinum Sensitivity ◽  
Cycle Arrest ◽  
Ovarian Cancers

AbstractTargeting PARP1 [Poly(ADP-Ribose) Polymerase 1] for synthetic lethality is a new strategy for BRCA germ-line mutated or platinum sensitive ovarian cancers. However, not all patients respond due to intrinsic or acquired resistance to PARP1 inhibitor. Development of alternative synthetic lethality approaches is a high priority. DNA polymerase β (Polβ), a critical player in base excision repair (BER), interacts with PARP1 during DNA repair. Here we show that polβ deficiency is a predictor of platinum sensitivity in human ovarian tumours. Polβ depletion not only increased platinum sensitivity but also reduced invasion, migration and impaired EMT (epithelial to mesenchymal transition) of ovarian cancer cells. Polβ small molecular inhibitors (Pamoic acid and NSC666719) were selectively toxic to BRCA2 deficient cells and associated with double-strand breaks (DSB) accumulation, cell cycle arrest and increased apoptosis. Interestingly, PARG [Poly(ADP-Ribose) Glycohydrolase] inhibitor (PDD00017273) [but not PARP1 inhibitor (Olaparib)] was synthetically lethal in polβ deficient cells. Selective toxicity to PDD00017273 was associated with poly (ADP-ribose) accumulation, reduced nicotinamide adenine dinucleotide (NAD+) level, DSB accumulation, cell cycle arrest and increased apoptosis. In human tumours, polβ-PARG co-expression adversely impacted survival in patients. Our data provide evidence that polβ targeting is a novel strategy and warrants further pharmaceutical development in epithelial ovarian cancers.

scholarly journals Effect of β,γ-CHF- and β,γ-CHCl-dGTP Halogen Atom Stereochemistry on the Transition State of DNA Polymerase β

Biochemistry ◽  
2012 ◽  
Vol 51 (43) ◽  
pp. 8491-8501 ◽  
Author(s):  
Keriann Oertell ◽  
Yue Wu ◽  
Valeria M. Zakharova ◽  
Boris A. Kashemirov ◽  
David D. Shock ◽  
...  
Keyword(s):  
Transition State ◽  
Dna Polymerase ◽  
Halogen Atom ◽  
Dna Polymerase Β
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